Project Description Current treatments for multiple myeloma suffer from rapid evolution of drug resistance and have major side effects such as degeneration of the nervous system and neutropenia (decrease in white blood cells, thereby predisposing patients to infections). Thus innovative drugs with fewer side effects and efficacy in refractory disease urgently need to be approved, especially when considering that the disease itself causes numerous end-organ toxicities in an elderly patient population. ONC201 is a clinical-stage, first-in-class small molecule with striking preclinical anti-cancer activity that is the most potent in multiple myeloma compared to other tumor types and is effective without causing side effects in animals. This novel compound imparts its antitumor effects through a unique, previously undiscovered mechanism of action that involves activation of the integrated stress response that multiple myeloma cells are very sensitive to. Several academic investigators at premier institutions have demonstrated the optimal preclinical profile of ONC201 in a multitude of models and have found that this drug is especially effective against B-cell malignancies, such as the orphan disease multiple myeloma. Therefore the safety, mechanism, and preclinical efficacy of ONC201 warrants clinical evaluation in a phase I/II trial in multiple myeloma patients who have limited treatment options. Phase I of the trial will perform dose-escalation to establish a safe treatment dose and phase II of the trial will evaluate the monoagent efficacy of ONC201 in relapsed/refractory multiple myeloma patients. The proposal has the following aims: Aim #1: To determine the recommended phase II dose (RP2D) and primary efficacy of ONC201 when administered orally once every 3 weeks; Aim #2: Evaluate the clinical efficacy of ONC201 in multiple myeloma. These studies will provide information for the formulation of a development path for ONC201 to treat relapsed/refractory multiple myeloma: pharmacokinetics, identification of safe dose for subsequent testing, type I biomarkers for patient selection, and type II biomarkers for evaluation of mechanism and kinetics of response. ONC201 represents a transformative treatment option for patients with relapsed/refractory multiple myeloma as a safe, mutation-agnostic, and orally active inducer of the integrated stress response in refractory cancers. This proposal seeks to make a novel anticancer agent available to patients in need of treatment options and will push the novel product towards commercialization that would open the availability of this drug to patients in need on a global scale. Furthermore, these studies will advance the field by enabling the clinical evaluation of a first-in-class representing a novel therapeutic mechanism that offers superior safety and efficacy that is orthogonal to available multiple myeloma therapies.